DNA Methylation of NDRG2 in Gastric Cancer and Its Clinical Significance

Chang, Xiaojing; Li, Zhenhua; Ma, Jinguo; Deng, Peng; Zhang, Shuanglong; Yu, Zhi; Chen, Jing; Dai, Dong‐Qiu

doi:10.1007/s10620-012-2393-z

Cited by 31 publications

(27 citation statements)

References 32 publications

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“…In accordance with previous studies3031, methylation of the NDRG2 promoter was found in various cancer types (Supplementary Table 7; Fig. 7a).…”

Section: Resultssupporting

confidence: 92%

“…The phosphorylation of Ser380/Thr382/Thr383 is also elevated in human fibromyomatous uteri and may be a contributory factor in the development of uterine leiomyomas47. Although it is not known whether these phosphorylation events are attributed to the functional inactivation of NDRG2 , decreased expression and promoter methylation of the NDRG2 gene have been reported in various types of cancer, such as liver cancers, gastric cancers, colon cancers and glioblastomas303148495051. Therefore, we hypothesize that in ATLL and other types of tumour cells without genetic alterations in the PI3K-AKT pathway, the suppression of NDRG2 transcription disrupts the negative regulation of PI3K-AKT signalling via sustained PTEN-Ser380/Thr382/Thr383 phosphorylation during tumour development (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

et al. 2014

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Constitutive phosphatidylinositol 3-kinase (PI3K)-AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the N-myc downstream-regulated gene 2 (NDRG2)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail. We show that NDRG2 is a PTEN-binding protein that recruits protein phosphatase 2A (PP2A) to PTEN. The expression of NDRG2 is frequently downregulated in ATLL, resulting in enhanced phosphorylation of PTEN at the Ser380/Thr382/Thr383 cluster and enhanced activation of the PI3K-AKT pathway. Given the high incidence of T-cell lymphoma and other cancers in NDRG2-deficient mice, PI3K-AKT activation via enhanced PTEN phosphorylation may be critical for the development of cancer.

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“…In accordance with previous studies3031, methylation of the NDRG2 promoter was found in various cancer types (Supplementary Table 7; Fig. 7a).…”

Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

et al. 2014

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“…We have determined 14-20% NDRG2 methylation frequency in grade I-III gliomas, whereas methylation markedly increased to 49 % in grade IV glioblastomas (Figure 1A). In addtion to studies in glioblastoma, a number of studies using various techniques have shown frequent NDRG2 promoter methylation in different cancer cell lines and tumor tissues such as anaplastic meningiomas (20%), liver cancer (77%), colon cancer (27%), oral squamous cell carcinoma (62%), colorectal (64%) and gastric cancer (54%) 4, 13, 24-27. NDRG2 promoter methylation was observed to be associated with higher malignancy grade in meningiomas, colon cancer, gastric cancer and, in agreement with our findings, in glioma tumors 4, 5, 24, 27.…”

Section: Discussionmentioning

confidence: 99%

Glioma Malignancy-Dependent NDRG2 Gene Methylation and Downregulation Correlates with Poor Patient Outcome

Skiriutė¹,

Steponaitis²,

Vaitkienė³

et al. 2014

J. Cancer

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Aims: NDRG2 (N-myc downstream regulated gene 2) gene is involved in important biological processes: cell differentiation, growth and apoptosis. Several molecular studies have shown NDRG2 as a promising diagnostic marker involved in brain tumor pathology. The aim of the study was to investigate how changes in epigenetic modification and activity of NDRG2 reflect on glioma malignancy and patient outcome. Methods: 137 different malignancy grade gliomas were used as the study material: 14 pilocytic astrocytomas grade I, 45 diffuse astrocytomas grade II, 29 anaplastic astrocytomas grade III, and 49 grade IV astrocytomas (glioblastomas). Promoter methylation analysis has been carried out by using methylation-specific PCR, whereas RT-PCR and Western-blot analyses were used to measure NDRG2 expression levels. Results: We demonstrated that NDRG2 gene methylation frequency increased whereas expression at both mRNA and protein levels markedly decreased in glioblastoma specimens compared to the lower grade astrocytomas. NDRG2 transcript and protein levels did not correlate with the promoter methylation state, suggesting the presence of alternative regulatory gene expression mechanisms that may operate in a tissue-specific manner in gliomas. Kaplan-Meier analyses revealed significant differences in survival time in gliomas stratified by NDRG2 methylation status and mRNA and protein expression levels. Conclusions: Our findings highlight the usefulness of combining epigenetic data to gene expression patterns at mRNA and protein level in tumor biomarker studies, and suggest that NDRG2 downregulation might bear influence on glioma tumor progression while being associated with higher malignancy grade.

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“…A number of studies using various techniques have shown that epigenetic silencing of the NDRG2 promoter has been found in the majority of primary tumors, and different cancer cell lines and other tumor tissues such as glioma (46.3 - 62%), primary gastric (54%) and colorectal carcinoma (64.28%) cancers [8–11]. NDRG2 promoter methylation was observed to be associated with the invasiveness in gastric and colorectal cancer and with the aggressiveness of glioma tumor [8–10]. However, our analysis has hown no significant association between NDRG2 gene methylation and pituitary adenoma invasiveness.…”

Section: Discussionmentioning

confidence: 99%

“…Also, NDRG2 upregulation was associated with Alzheimer's disease or cerebral ischemia [21, 22]. Several studies have shown NDRG2 promoter CpG island methylation and down-regulation in liver [13], gastric [10], colorectal cancers (CRC) [23, 24], glioblastomas [8, 9] and anaplastic meningioma [25]. However, NDRG2 promoter methylation and mRNA expression levels in PAs has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

N-myc downstream-regulated gene 2 (NDRG2) promoter methylation and expression in pituitary adenoma

et al. 2017

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BackgroundPituitary adenoma (PA) is a benign primary tumor that arises from the pituitary gland and is associated with ophthalmological, neurological and endocrinological abnormalities. However, causes that increase tumor progressing recurrence and invasiveness are still undetermined. Several studies have shown N-myc downstream regulated gene 2 (NDRG2) as a tumor suppressor gene, but the role of NDRG2 gene in pituitary adenoma pathogenesis has not been elucidated. The aim of our research has been to examine NDRG2 mRNA expression in PA and to determine the associations between the NDRG2 gene epigenetic changes and the development of recurrence or invasiveness of PA and patient clinical data.MethodsThe MS-PCR was used for NDRG2 promoter methylation analysis and gene mRNA expression levels were evaluated by qRT-PCR in 68 non-functioning and 73 functioning adenomas. Invasiveness was evaluated using magnetic resonance imaging with Hardy’s modified criteria. Statistical analysis was performed to find correlations between NDRG2 gene mRNA expression, promoter methylation and patient clinical characteristics and PA activity.ResultsThe NDRG2 mRNA expression was significantly lower in the case of acromegaly (GH and IGF-1 hypersecretion) than in other diagnoses of PAs (p < 0.05). Also, the NDRG2 expression was significantly higher in prolactinoma (PRL hypersecretion) than in in other diagnoses of PAs (p < 0.05). The promoter of NDRG2 was methylated in 22.69% (12/58 functioning and 15/61 non-functioning) of patients with PA. However, the NDRG2 gene mRNA expression was not significantly related to its methylation status. Clinical factors, such as: age, gender, relapse and diagnoses of Cushing syndrome were of no significance for NDRG2 promoter methylation and mRNA expression levels, as well as secreting or non-secreting PAs and the invasiveness of PAs.ConclusionThe different NDRG2 promoter methylation and expression levels in PA samples showed tumor heterogeneity and indicates a potential role of this gene in pituitary adenoma pathogenesis, but the corresponding details require intensive research.

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DNA Methylation of NDRG2 in Gastric Cancer and Its Clinical Significance

Abstract: Our results suggest that the aberrant methylation of NDRG2 may be mainly responsible for its downregulation in gastric cancer, and may play an important role in the metastasis of gastric cancer.

Cited by 31 publications

References 32 publications

Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

Glioma Malignancy-Dependent NDRG2 Gene Methylation and Downregulation Correlates with Poor Patient Outcome

N-myc downstream-regulated gene 2 (NDRG2) promoter methylation and expression in pituitary adenoma

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